Changes in the epidemiology of hepatitis A: Clinical and preventive implications. / Cambios en la epidemiología de la hepatitis A: repercusiones clínicas y preventivas.

INTRODUCTION AND OBJECTIVES: Hepatitis A Virus Infection (HAI) has been related to the hygienic-sanitary situation of an area, the changes in the epidemiology of HAI in the province of Guadalajara between 1991 and 2017 are analyzed. MATERIALS AND METHODS: Cases of HAI declared between 1991 and 2017 in Guadalajara were included. The variables analyzed were age, sex, environment, risk factors for HAI and need for hospitalization. The incidence was compared in three periods: 1991-1999, 2000-2008 and 2009-2017. RESULTS: Two hundred and thirty-three cases of HAI were declared, the average incidence rate was 4.27 cases/100,000 inhabitants, highest between 1991 and 1999 (6.93) and lowest between 2009 and 2017 (1.92), with an increment in 2017 (5.5). The median age was 16 years (IR: 8.5-28.5 years), 58.4% were male, and the highest incidence occurred between 5 and 14 years in both sexes. The most frequent risk factors were family and non-family contact and trips to endemic areas (18.6%, 17.3% and 18.2%, respectively). The last risk factor increased after 2000 (P=.001), as did the incidence in urban areas. The MSM group showed an increase in the last period (P<.001). Hospital admissions increased progressively from the first to the third period studied (P=.001). CONCLUSIONS: HAI has a low incidence in our area. More cases related to travel or sexual practices are observed. This should be considered when establishing prevention policies, including vaccination of the most exposed people.

The natural matching of harmonic responses in the pulmonary circulation.

KEY POINTS: The right ventricle of the mammal heart is highly sensitive to the afterload imposed by a combination of the pulmonary circulation and the retrograde contribution of the left heart. Right ventricular afterload can be analysed in terms of pulmonary artery input impedance, which we were able to decompose as the result of the harmonic frequency responses of the pulmonary vessels and the left heart attached in series. Using spectral methods, we found a natural matching between the pulmonary vasculature and the left chambers of the heart. This coupling implies that the upstream transmission of the left heart frequency-response has favourable effects on the pulmonary tree. This physiological mechanism protects the right ventricle against acute changes in preload, and its impairment may be a relevant contribution to right ventricle dysfunction in pulmonary hypertension. ABSTRACT: The right ventricle (RV) of the mammal heart is highly sensitive to the afterload imposed by the pulmonary circulation, and the left heart (LH) retrogradely contributes significantly to this vascular load. Transmission-line theory anticipates that the degree of matching between the frequency responses of the pulmonary vasculature and the LH should modulate the global right haemodynamic burden. We measured simultaneous high-fidelity flow (pulmonary artery) and pressure (pulmonary artery and left atrium) in 18 healthy minipigs under acute haemodynamic interventions. From these data, we decomposed the impedance spectra of the total right-circulation system into the impedance of the pulmonary vessels and the harmonic response of the LH. For frequencies above the first harmonic, total impedance was below the pulmonary impedance during all phases (P < 0.001; pooled phases), demonstrating a favourable effect of the LH harmonic response on RV pulsatile load: the LH harmonic response was responsible for a 20% reduction of pulse pulmonary artery pressure (P < 0.001 vs. a theoretical purely-resistive response) and a 15% increase of pulmonary compliance (P = 0.009). This effect on compliance was highest during acute volume overload. In the normal right circulation, the longitudinal impedance of the pulmonary vasculature is matched to the harmonic response of the LH in a way that efficiently reduces the pulmonary pulsatile vascular load. This source of interaction between the right and left circulations of mammals protects the RV against excessive afterload during acute volume transients and its disruption may be an important contributor to pulmonary hypertension.

Left ventricular systolic function is associated with sympathetic nervous activity and markers of inflammation in cirrhosis.

An accurate evaluation of cardiac function in patients with cirrhosis remains a challenge. We used robust echocardiographic indices to characterize left ventricular (LV) systolic function and its relationship to activation of the sympathetic nervous system and inflammation in 59 patients with cirrhosis and 59 age-matched controls. Additionally, in 11 patients we withdrew beta-blockers and diuretics and used phenylephrine and albumin infusion to evaluate the response to acute afterload and preload changes (interventional substudy). Measures of systolic LV function such as the ejection intraventricular pressure difference (EIVPD) and the systolic strain rate were higher in patients with cirrhosis than in controls (median [1st-3rd quartile], 4.0 [3.1-5.1] versus 2.9 [2.4-3.6] mm Hg and -1.3 [-1.6 to -1.1] versus -1.2 [-1.6 to -1.1)] s-1 , respectively; P < 0.05 for both). EIVPD was related to the severity of liver disease (Model for End-Stage Liver Disease, rho = 0.45, P < 0.001), the degree of sympathetic nervous system activation (noradrenaline, rho = 0.26, P = 0.05; heart rate variability, rho = -0.43, P = 0.003), and treatment with beta-blockers (P = 0.001). In the interventional substudy, EIVPD was higher in patients with ascites (6.5 [5.4-8.5] versus 4.0 [3.9-5.1] mm Hg, P = 0.045). The decrease in EIVPD induced by phenylephrine was inversely related to baseline systolic function (P < 0.05) and associated with markers of systemic vasodilatation (nitric oxide, rho = -0.66, P = 0.06; diastolic blood pressure, rho = 0.68, P = 0.04) and inflammation (interleukin-1beta, rho = -0.80, P = 0.009). CONCLUSION: LV systolic function is enhanced in cirrhosis due to augmented adrenergic tone and modulated by treatment with beta-blockers; acute afterload stress induces a deeper impairment of systolic function in patients with more advanced degrees of vasodilatation and inflammation; these changes in LV function related to cirrhosis can be assessed using robust echocardiographic methods. (Hepatology 2017;65:2019-2030).

Alteration profile of executive functions in multiple sclerosis.

OBJECTIVE: Executive functions (EF) in multiple sclerosis (MS) have been only partially studied, mainly trough the evaluation of subfunctions. The main objective was to analyse the EF alteration profile in a patients with MS sample. PARTICIPANTS AND METHODS: Case-control study, 100 patients with MS and 30 controls were evaluated by the following tests: Comprehensive Trail Making Test, Stroop Test, Wisconsin Card Sorting Test, picture completion, letter-number sequencing, comprehension and similarities of the WAIS-III scale, phonological and semantic fluency, zoo map test, temporal judgment and behavioural Dysexecutive Questionnaire (DEX-Q) of the Behavioural Assessment of the Dysexecutive Syndrome. Scores below normative values were considered pathological. Factorial analysis was used to simplify the deficits, and multiple regression and ANOVA statistics were used to analyse the relationship between clinical and cognitive variables. RESULTS: Seventy-four patients had a recurrent-relapsing course, the mean degree of disability by Expanded disability Status Scale (EDSS) was 2.7 and the mean time of evolution was 9.94 years. Eighty-five per cent presented alterations in 3 or more EF tests and 71% in 5 or more. In the factorial analysis, three groups of functions were involved: (i) cognitive flexibility (ii) inhibition and (iii) abstraction ability. Patients with a progressive course and a high EDSS had a significantly worse performance (P < 0.05). The patients showed a low awareness of their deficit in the DEX-Q. CONCLUSIONS: Cognitive flexibility, inhibition and abstraction ability were the three components of EF most deficient. The patients with the worst performance were those with progressive forms and a high EDSS.

Intraventricular vortex properties in nonischemic dilated cardiomyopathy.

Vortices may have a role in optimizing the mechanical efficiency and blood mixing of the left ventricle (LV). We aimed to characterize the size, position, circulation, and kinetic energy (KE) of LV main vortex cores in patients with nonischemic dilated cardiomyopathy (NIDCM) and analyze their physiological correlates. We used digital processing of color-Doppler images to study flow evolution in 61 patients with NIDCM and 61 age-matched control subjects. Vortex features showed a characteristic biphasic temporal course during diastole. Because late filling contributed significantly to flow entrainment, vortex KE reached its maximum at the time of the peak A wave, storing 26 ± 20% of total KE delivered by inflow (range: 1-74%). Patients with NIDCM showed larger and stronger vortices than control subjects (circulation: 0.008 ± 0.007 vs. 0.006 ± 0.005 m(2)/s, respectively, P = 0.02; KE: 7 ± 8 vs. 5 ± 5 mJ/m, P = 0.04), even when corrected for LV size. This helped confining the filling jet in the dilated ventricle. The vortex Reynolds number was also higher in the NIDCM group. By multivariate analysis, vortex KE was related to the KE generated by inflow and to chamber short-axis diameter. In 21 patients studied head to head, Doppler measurements of circulation and KE closely correlated with phase-contract magnetic resonance values (intraclass correlation coefficient = 0.82 and 0.76, respectively). Thus, the biphasic nature of filling determines normal vortex physiology. Vortex formation is exaggerated in patients with NIDCM due to chamber remodeling, and enlarged vortices are helpful for ameliorating convective pressure losses and facilitating transport. These findings can be accurately studied using ultrasound.

[Re-emergence of measles in the province of Guadalajara, Spain. Is it time to establish new strategies for its elimination?]. / Reemergencia de sarampión en la provincia de Guadalajara. ¿Es el momento de establecer nuevas estrategias para su eliminación?

BACKGROUND: Measles is a viral infection that was almost eradicated, but it is re-emerging in Spain and Europe in recent years. The aim of this study was to describe the microbiological, clinical and epidemiological characteristics of a measles outbreak that occurred in Guadalajara (Spain) from June to August 2012. METHODS: A descriptive and retrospective study was conducted. A total of 117 samples (including serum, urine and pharyngeal swabs) from 52 patients were analyzed for measles. RESULTS: Measles was diagnosed in 50 patients, 41 of them by microbiological diagnosis, and 9 by epidemiological link. The patients were grouped in four community outbreaks. No imported cases were observed. Positive IgM and positive CRP were detected in 25 patients, positive CRP only in 11 and positive IgM only in 5. The genotype D4 was identified in 13 patients and the genotype A in a post-vaccine case. The age groups most affected were adults between 20-34 years of age (38%) and younger than 15 months (26%). The large majority (86%) of patients were unvaccinated (44% Roma population, 27% younger than 15 months, 11% ideological reasons), 6% had one vaccine dose. The signs/symptoms were: rash and fever, 100%, cough, 82%, and conjunctivitis 50%. Almost one-third (32%) of patients were hospitalized, and 28% had complications. CONCLUSIONS: It is very important to intensify the epidemiological surveillance of infections in the elimination phase. The increased incidence of measles was associated to unvaccinated pockets, presenting a challenge for Public Health Centers. These agencies should prepare strategies to obtain a higher vaccine coverage for the eradication of measles.

Sufficiency for PSS tracking gait disorders in multiple sclerosis: A managerial perspective.

This study primarily aimed to explore the capabilities of digitalisation in the healthcare context, focusing on a specific disease. In this case, the study examined the potential of remote monitoring of gait to address the sensitivity of multiple sclerosis progression to gait characteristics by adopting a non-invasive approach to remotely quantify gait disturbances in a patient's daily life. To better understand the managerial aspects associated with this approach, the researchers conducted a literature review along with a set of semi-structured interviews. The target population included MS patients as well as the key agents involved in their care: patients' family members, neurologists, MS nurses, physiotherapists, medical directors, and pharmacist. The study identifies the perceived barriers and drivers that could contribute to the successful deployment of PSS remote gait monitoring as a healthcare service: i) At mega-level governance. Implications on privacy and security data are notable barriers missing on the speech. ii) At macro level, funding is highlighted as main barrier. The cost and lack of health system subsidies may render initiatives unsustainable, as emphasised by the interviewees. iii) At meso level, useable data is recognised as a driver. The data collection process can align with diverse interests to create value and business opportunities for the ecosystem actors, enhance care, attract stakeholders, such as insurers and pharma, and form partnerships. iv) At micro-level processes, we find two potential barriers: wearable device and app usability (comfort, navigation, efficiency) and organisational/behavioural aspects (training, digital affinity, skills), which are crucial for value creation in innovation ecosystems among patients and healthcare professionals. Finally, we find an interesting gap in the literature and interviews. Stakeholders' limited awareness of technological demands, especially from information technologies, for a successful long-term service, can be consider two key barriers for PSS.

Assisted Reproductive Techniques in Multiple Sclerosis: Recommendations from an Expert Panel.

INTRODUCTION: Multiple sclerosis (MS) is mainly diagnosed in women of reproductive age. However, there is a paucity of guidelines jointly prepared by neurologists and gynaecologists on managing women with MS and the desire for motherhood. Therefore, in this review we propose recommendations for such cases, with an particular focus on those requiring assisted reproductive techniques (ART). METHODS: A group of seven MS experts (4 neurologists and 3 gynaecologists) came together for three discussion sessions to achieve consensus. RESULTS: The recommendations reported here focus on the importance of early preconception counselling, the management of disease-modifying therapies before and during ART procedures, important considerations for women with MS regarding ART (intrauterine insemination, in vitro fertilisation and oocyte cryopreservation) and the paramount relevance of multidisciplinary units to manage these patients. CONCLUSIONS: Early preconception consultations are essential to individualising pregnancy management in women with MS, and an early, well-planned, spontaneous pregnancy should be the aim whenever possible. The management of women with MS and the desire for motherhood by multidisciplinary units is warranted to ensure appropriate guidance through the entire pregnancy.

MicroRNAs Associated with Disability Progression and Clinical Activity in Multiple Sclerosis Patients Treated with Glatiramer Acetate.

MicroRNAs (miRNAs) are promising biomarkers in multiple sclerosis (MS). This study aims to investigate the association between a preselected list of miRNAs in serum with therapeutic response to Glatiramer Acetate (GA) and with the clinical evolution of a cohort of relapsing-remitting MS (RRMS) patients. We conducted a longitudinal study for 5 years, with cut-off points at 2 and 5 years, including 26 RRMS patients treated with GA for at least 6 months. A total of 6 miRNAs from a previous study (miR-9.5p, miR-126.3p, mir-138.5p, miR-146a.5p, miR-200c.3p, and miR-223.3p) were selected for this analysis. Clinical relapse, MRI activity, confirmed disability progression (CDP), alone or in combination (No Evidence of Disease Activity-3) (NEDA-3), and Expanded Disability Status Scale (EDSS), were studied. After multivariate regression analysis, miR-9.5p was associated with EDSS progression at 2 years (ß = 0.23; 95% CI: 0.04-0.46; p = 0.047). Besides this, mean miR-138.5p values were lower in those patients with NEDA-3 at 2 years (p = 0.033), and miR-146a.5p and miR-126.3p were higher in patients with CDP progression at 2 years (p = 0.044 and p = 0.05 respectively. These results reinforce the use of microRNAs as potential biomarkers in multiple sclerosis. We will need more studies to corroborate these data and to better understand the role of microRNAs in the pathophysiology of this disease.

Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL.

OBJECTIVE: Calcific aortic valve disease is similar to atherosclerosis in that both diseases result from chronic inflammation and endothelial dysfunction. Heterozygous NOTCH1 mutations have been associated to calcific aortic disease and a bicuspid aortic valve. We investigated whether mice with genetic inactivation of the Notch signaling pathway are prone to develop valve disease when exposed to a predisposing diet. METHODS AND RESULTS: Using Doppler echocardiography, histology, immunohistochemistry, quantitative gene expression analysis, and cell culture assays, we examined the effect of a hypercholesterolemic diet supplemented with vitamin D on mice heterozygous for null mutations in the Notch1 receptor or the effector transcription factor gene RBPJk. After 16 weeks on the hyperlipidemic diet, calcific aortic disease was detected in heterozygous RBPJk mice. Analysis of valve leaflets revealed macrophage infiltration, enhanced collagen deposition, proosteogenic protein expression, and calcification. Heterozygous null Notch1 mice displayed milder histopathologic changes and did not develop any significant hemodynamic disturbance. Valvular disease correlated with reduced expression of the Notch target gene Hey1 in valves of RBPJk heterozygous mice fed the hyperlipidemic diet. Consistent with the in vivo data, Notch signaling inhibition in porcine valve interstitial cells led to downregulation of HEY1 transcription, activation of osteogenic markers, and increased calcified nodule formation. CONCLUSIONS: We show that Notch signaling disruption via RBPJk heterozygous inactivation results in aortic valve disease. Notch1 heterozygous mice do not show functional impairment, suggesting that additional Notch receptors may be involved in aortic valve homeostasis and disease. Our data establish a genetic mouse model of calcific aortic valve disease and may help to identify a patient population with reduced valvular NOTCH signaling at risk for developing this disease.

Risk and prognostic factors for SARS-CoV-2 infection in Spanish population with multiple sclerosis during the first five waves.

Background: Data on coronavirus disease 2019 (COVID-19) incidence in patients with multiple sclerosis (MS) during the first wave have been published but are scarce for the remaining waves. Factors associated with COVID-19 infection of any grade are also poorly known. The aim of this study was to analyze the incidence, clinical features, and risk factors for COVID-19 infection of any grade in patients with MS (pwMS) during waves 1-5. Methods: This study prospectively analyzes the cumulative incidence of COVID-19 from the first to the fifth waves by periodic case ascertainment in pwMS followed at the University Hospital of Getafe (UHG). Global and stratified cumulative incidence was calculated. Logistic regression models were used to estimate the weight of selected variables as risk and prognostic factors. Results: We included 431 pwMS, of whom 86 (20%) were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The overall cumulative incidence of confirmed cases was similar to that of Madrid (13,689 vs. 13,307 per 100,000 habitants) but 3 times higher during the first wave and slightly lower from the second to the fifth waves. The majority (86%) of pwMS developed mild forms of COVID-19. Smoking was the only factor associated with a decreased risk of SARS-CoV2 infection of any grade [odds ratio (OR) 0.491; 95% CI 0.275-0.878; p = 0.017]. Risk factors associated with severe forms were Expanded Disability Severity Scale (EDSS) ≥3.5 (OR 7.569; 95% CI 1.234-46.440) and pulmonary disease (OR 10.763; 95% CI 1.27-91.254). Conclusion: The incidence of COVID-19 was similar in this MS cohort to the general population. Smoking halved the risk of being infected. Higher EDSS and pulmonary comorbidity were associated with an increased risk of severe forms.

microRNA Expression and Its Association With Disability and Brain Atrophy in Multiple Sclerosis Patients Treated With Glatiramer Acetate.

Background: MicroRNAs are small non-coding RNA that regulate gene expression at a post-transcriptional level affecting several cellular processes including inflammation, neurodegeneration and remyelination. Different patterns of miRNAs expression have been demonstrated in multiple sclerosis compared to controls, as well as in different courses of the disease. For these reason they have been postulated as promising biomarkers candidates in multiple sclerosis. Objective: to correlate serum microRNAs profile expression with disability, cognitive functioning and brain volume in patients with remitting-relapsing multiple sclerosis. Methods: cross-sectional study in relapsing-remitting multiple sclerosis patients treated with glatiramer acetate. Disability was measured with Expanded Disability Status Scale (EDSS) and cognitive function was studied with Symbol Digit Modalities Test (SDMT). Brain volume was analyzed with automatic software NeuroQuant®. Results: We found an association between miR.146a.5p (rs:0.434, p=0.03) and miR.9.5p (rs:0.516, p=0.028) with EDSS; and miR-146a.5p (rs:-0.476, p=0.016) and miR-126.3p (rs:-0.528, p=0.007) with SDMT. Regarding to the brain volume, miR.9.5p correlated with thalamus (rs:-0.545, p=0.036); miR.200c.3p with pallidum (rs:-0.68, p=0.002) and cerebellum (rs:-0.472, p=0.048); miR-138.5p with amygdala (rs:0.73, p=0.016) and pallidum (rs:0.64, p=0.048); and miR-223.3p with caudate (rs:0.46, p=0.04). Conclusions: These data support the hypothesis of microRNA as potential biomarkers in this disease. More studies are needed to validate these results and to better understand the role of microRNAs in the pathogenesis, monitoring and therapeutic response of multiple sclerosis.

Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate.

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.

Intraventricular Flow Patterns in Patients Treated with Left Ventricular Assist Devices.

The success of left ventricular assist device (LVAD) therapy is hampered by complications such as thrombosis and bleeding. Understanding blood flow interactions between the heart and the LVAD might help optimize treatment and decrease complication rates. We hypothesized that LVADs modify shear stresses and blood transit in the left ventricle (LV) by changing flow patterns and that these changes can be characterized using 2D echo color Doppler velocimetry (echo-CDV). We used echo-CDV and custom postprocessing methods to map blood flow inside the LV in patients with ongoing LVAD support (Heartmate II, N = 7). We compared it to healthy controls (N = 20) and patients with dilated cardiomyopathy (DCM, N = 20). We also analyzed intraventricular flow changes during LVAD ramp tests (baseline ± 400 rpm). LVAD support reversed the increase in blood stasis associated with DCM, but it did not reduce intraventricular shear exposure. Within the narrow range studied, the ventricular flow was mostly insensitive to changes in pump speed. Patients with significant aortic insufficiency showed abnormalities in blood stasis and shear indices. Overall, this study suggests that noninvasive flow imaging could potentially be used in combination with standard clinical methods for adjusting LVAD settings to optimize flow transport and minimize stasis on an individual basis.

Predicting conversion to multiple sclerosis by assessing cognitive impairment in radiologically isolated syndrome.

Up to a third of patients with radiologically isolated syndrome (RIS) exhibit lower-than-expected cognitive performances in neuropsychological evaluations, but the relationship between cognitive impairment (CI) and quantitative magnetic resonance (MRI) measures has not been stablished. Furthermore, the prognostic role of CI in RIS for conversion to MS is currently unknown. We assessed 17 patients with RIS and 17 matched healthy controls (HC) with a neurophychological battery and a 3T MRI. Six patients (35,3%) fulfilled our criterion for CI (scores 2 SDs below the mean of HC in at least two cognitive tests) (ci-RIS). The ci-RIS subgroup showed lower values of normalized brain and gray matter volumes when compared to HC. After a median follow-up time of 4.5 years, the ci-RIS subgroup presented a higher conversion rate to MS, suggesting that CI might be an independent risk factor for conversion to MS.

Cancer diagnosis in a Spanish cohort of multiple sclerosis patients under dimethylfumarate treatment.

BACKGROUND: Potential increase of cancer incidence is one of the main safety concerns of the disease-modifying therapies employed in Multiple Sclerosis (MS). OBJECTIVE: Detailed description of patients who developed cancer among a prospective cohort of Spanish MS patients on dimethyl fumarate (DMF) treatment. METHODS: We describe patients who developed cancer among a cohort of 886 MS patients on DMF treatment (2681 patient-years), with a median time of exposure of 39.5 months (IQR 23-51.5), who participated in a multicentre and prospective real-world study conducted in 16 Spanish National Health System hospitals from February 2014 to May 2019. Local researchers were periodically contacted by the investigation team to monitor safety issues. Cancer histories were collected from the medical records and the information was updated at July 30th 2020. RESULTS: Eight Caucasian women developed cancer, which accounts for 0.9% and an accumulated malignancy rate of 298.39 cases per 100,000 patient-years of DMF exposure. At the time of cancer diagnosis, age was between 33 to 67 years and median time on DMF treatment 16.5 months (range 1-53). Two patients had familiar history of cancer. No specific cancer lines were found (breast cancer in 2 cases, thyroid in 3, urothelial carcinoma, cervix and a progression to leiomyosarcoma from a mitotically active leiomyoma). DMF was withdrawn during cancer treatment in 6 patients and reintroduced later. All cancers except one are in complete remission. The patient with leiomyosarcoma died by cancer progression. CONCLUSION: A relationship between cancers and DMF is unlikely because the malignancy rate was similar to that of the age-and sex-matched general population, and because of the absence of specific tumour cell lines. Nevertheless, as with other immunosuppressive DMTs, clinicians treating MS should be aware of any potential cancer symptom and demand proper testing.

Blood Stasis Imaging Predicts Cerebral Microembolism during Acute Myocardial Infarction.

BACKGROUND: Cardioembolic stroke is a major source of mortality and disability worldwide. The authors hypothesized that quantitative characterization of intracardiac blood stasis may be useful to determine cardioembolic risk in order to personalize anticoagulation therapy. The aim of this study was to assess the relationship between image-based metrics of blood stasis in the left ventricle and brain microembolism, a surrogate marker of cardiac embolism, in a controlled animal experimental model of acute myocardial infarction (AMI). METHODS: Intraventricular blood stasis maps were derived from conventional color Doppler echocardiography in 10 pigs during anterior AMI induced by sequential ligation of the mid and proximal left anterior descending coronary artery (AMI-1 and AMI-2 phases). From these maps, indices of global and local blood stasis were calculated, such as the average residence time and the size and ratio of contact with the endocardium of blood regions with long residence times. The incidence of brain microemboli (high-intensity transient signals [HITS]) was monitored using carotid Doppler ultrasound. RESULTS: HITS were detected in 0%, 50%, and 90% of the animals at baseline and during AMI-1 and AMI-2 phases, respectively. The average residence time of blood in the left ventricle increased in parallel. The residence time performed well to predict microemboli (C-index = 0.89, 95% CI, 0.75-1.00) and closely correlated with the number of HITS (R = 0.87, P < .001). Multivariate and mediation analyses demonstrated that the number of HITS during AMI phases was best explained by stasis. Among conventional echocardiographic variables, only apical wall motion score weakly correlated with the number of HITS (R = 0.3, P = .04). Mural thrombosis in the left ventricle was ruled out in all animals. CONCLUSIONS: The degree of stasis of blood in the left ventricle caused by AMI is closely related to the incidence of brain microembolism. Therefore, stasis imaging is a promising tool for a patient-specific assessment of cardioembolic risk.

Executive function and memory in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system very heterogeneous in its characteristics. In contrast to the well known sensitive/motor deficits, the cognitive dysfunction has only been analyzed in the last few decades. Attention, executive function, and memory were assessed in 28 patients with recurrent-remittent MS (RRMS) (duration, median 7 years; EDSS median 2) by means of a specific neuropsychological battery. Depression (BDI), anxiety (STAI) and fatigue (FSS) were also assessed. Twenty-five of these patients were selected for statistical study because they presented deficits in some cognitive areas. Twenty-four percent of the patients displayed memory deficits and 80% showed attention and executive function deficits related to prefrontal lobe function. No global memory difficulties were found, except for immediate visual memory of complex elements (immediate recall of the Rey figure), although the visual reproduction I subtest of the WMS-R was unaffected. In RRMS patients with a relatively short duration and low level of incapacity, cognitive impairments mainly affected prefrontal functions. The difficulties in immediate visual memory of complex elements could also be explained by a failure in these areas, due to the alteration of the organization and strategic use of the material to be encoded.

Age-Dependence of Flow Homeostasis in the Left Ventricle.

Background: Intracardiac flow homeostasis requires avoiding blood stasis and platelet activation during its transit through the cardiac chambers. However, the foundations of intraventricular blood washout and its exposure to shear stresses have been poorly addressed. We aimed to characterize and quantify these features in a wide population of healthy subjects and assess the relationships of these indices with age. Methods: We used color-Doppler echocardiography and custom post-processing methods to study 149 healthy volunteers from 26 days to 80 years old. From the intraventricular flow-velocity fields we obtained personalized maps of (1) the residence time of blood in the LV, and (2) the shear index, a metric accounting for the strongest occurrence of shear stresses inside the chamber. From these maps we derived quantitative indices of the overall intraventricular blood washout and shear exposure. We addressed the age-dependence of these indices and analyzed their relationship with age-related changes in filling-flow. Results: The entire intraventricular blood pool was replaced before 8 cycles. Average residence time of blood inside the LV was <3 cycles in all subjects and followed an inverse U-shape relationship with age, increasing from median (IQR) of 1.0 (0.7 to 1.2) cycles in the 1st year of life to 1.8 (1.4-2.2) cycles in young adults (17-30 years old), becoming shorter again thereafter. Shear index showed no relation with age and was bounded around 20 dyn·s/cm2. Regions with the longest residence time and highest shear index were identified near the apex. Differences in the degree of apical penetration of the filling waves and the duration of the late-filling phase explained the age-dependence of residence time ( R adj 2 = 0.48, p < 0.001). Conclusions: In average, blood spends 1 to 3 beats inside the LV with very low shear stress rates. The apical region is the most prone to blood stasis, particularly in mid-aged adults. The washout of blood in the normal LV is age-dependent due to physiological changes in the degree of apical penetration of the filling waves.

Valve area and the risk of overestimating aortic stenosis.

OBJECTIVE: To obtain reference values of aortic valve area (AVA) in a large population and to infer the risk of overestimating aortic stenosis (AS) when focusing on flow-corrected indices of severity. METHODS: We prospectively measured indices of AS in all consecutive echocardiograms performed in a large referral cardiac imaging laboratory for 1 year. We specifically analysed the distribution of AVA, indexed AVA and velocity ratio (Vratio) in patients with and without AS, the latter defined as the coexistence of valvular outflow obstruction (Vmax ≥2.5 m/s) and morphological findings of valve degeneration. RESULTS: 16 156 echocardiograms were analysed, 14 669 of which did not show valvular obstruction (peak jet velocity <2.5 m/s). In the latter group, AVA was 2.6±0.7 cm2 in 8190 studies with normal valves and 2.3±0.7 cm2 in 6479 studies with aortic sclerosis (AScl). There was a relatively wide overlap between values of AVA, indexed AVA and velocity ratio between studies of patients with AScl and AS. Values of AVA ≤1.0 cm2 were found in 0.5% of studies with normal valves and 1.8% of studies with AScl. These proportions were 3.1% and 9.3% for AVA ≤1.5 cm2, respectively. Vratio ≤0.25 were found in 0.1% of patients without obstruction. Risk factors for a small AVA in patients without obstruction were AScl, female sex, small body surface area, low ejection fraction and mitral regurgitation. CONCLUSIONS: Normal values of continuity-equation derived AVA are smaller than previously considered. AVA values below cutoffs of moderate or severe AS can be found in patients without the disease. Flow-corrected indices may overestimate AS in patients with low gradients, particularly in the presence of well-identified risk factors.